Advanced chronic renal disease in humans is typically associated with multiple endocrine and metabolic abnormalities. Conventional therapy for treating chronic renal failure has focused on protein-restricted diets in conjunction with administration of ketoacid analogs of amino acids; see U.S. Pat. Nos. 4,100,160, 4,228,099 and 4,352,814, all of Walser, and U.S. Pat. No. 4,752,619 of Walser et al.
Another technique for slowing the progression of chronic renal failure is described by Walser in U.S. Pat. No. 5,175,144 and in U.S. application Ser. No. 07/996,757, where the treatment involves administration of ketoconazole or other agent that suppresses glucocorticoid production.
Although these therapies may be useful in slowing the progression of chronic renal failure in many patients, the mechanism and factors that lead to chronic renal failure are still not well understood.
The human adrenal cortex secretes a variety of steroid hormones, including androgens, glucocorticoids and mineralocorticoids. The predominant androgen produced by the adrenal cortex is dehydroepiandrosterone (DHEA). DHEA is a nineteen carbon atom steroid hormone that is well known to serve as the precursor of sex hormones such as testosterone, dihydrotestosterone, estradiol and estrone.
In recent years, many studies have been undertaken to elucidate the biological role of DHEA. The results of this research are far from conclusive but suggest that DHEA has many diverse biological, biochemical and physiological effects involving various cell types, tissues and organs.
A review article by Meikle et al. in "Adrenal Androgen Secretion and Biologic Effects ," Endrocrinol. Metab. Clinics N. Amer., 20:381-400 (1991), describes some of the biologic effects of DHEA and underscores the fact that its normal functions are not well understood.
DHEA studies involving laboratory rats or mice have reported that administration of DHEA prevents obesity, inhibits tumor development, ameliorates diabetes, prevents autoimmune anemia, prevents double-stranded DNA antibody formation and prolongs survival in lupus erythematosus-susceptible mice (see for example, Meikle et al. (supra); Lucas et al., J. Clin. Invest., 75:2091-2093 (1985); and Svec et al., Proc. Soc. Exp. Med. Biol., 209:92-97 (1995)).
A recent study in humans by van Vollenhoven et al., "An Open Study of Dehydroepiandrosterone in Systemic Lupus Erythematosus," Arthritis Rheum., 37:1305-1310 (1994), confirmed early animal studies that DHEA was useful in treating mild to moderate systemic lupus erythematosus. Three of the ten patients in the study also had proteinuria, which was improved by the administration of DHEA.
The Meikle et al. review article (supra) likewise mentions, in its discussion under renal effects, that aging laboratory rats, which typically develop proteinuria, had this condition reduced by long term treatment with DHEA.
Studies of patients with chronic renal failure have reported that plasma levels of the adrenal androgen DHEA in such patients are low (see Zumoff et al., "Subnormal Plasma Adrenal Androgen Levels in Men With Uremia," J. Clin. Endocrinol. Metab., 51:801-805 (1980)) but that the adrenal gland secretory capacity for production of DHEA and of other adrenal androgens and steroids is undiminished, as demonstrated by stimulation with a known adrenal stimulus, cosyntropin (see Winer et al., "Preservation of Normal Adrenal Androgen Secretion in End Stage Renal Disease," Metabolism, 31:269-273 (1982)).
Meikle et al. (supra) report that studies have shown that DHEA levels in the body are significantly reduced by the administration of a synthetic glucocorticoid. A recent study of the biologic effects of DHEA identified an anti-glucocorticoid effect of DHEA but concluded that minimal information was available on the cellular and molecular mechanism of DHEA; see Kalimi et al., "Anti-glucocorticoid Effects of Dehydroepiandrosterone (DHEA)", Mol. Cell. Biochem., 131:99-104 (1994).
One reported medical use for DHEA is as a topical treatment for preventing dry skin, described in U.S. Pat. Nos. 4,496,556 and 4,542,129 of Orentreich. The former patent notes that oral ingestion of DHEA results in the undesirable increase in oil production by all sebaceous glands over the entire body.
These reports in the prior art fail to suggest any usefulness of DHEA in the context of a treatment method for retarding the progression of chronic renal failure.